CN102665406A - Methods for the synthesis of polycyclic guanidine compounds - Google Patents

Methods for the synthesis of polycyclic guanidine compounds Download PDF

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CN102665406A
CN102665406A CN2010800584737A CN201080058473A CN102665406A CN 102665406 A CN102665406 A CN 102665406A CN 2010800584737 A CN2010800584737 A CN 2010800584737A CN 201080058473 A CN201080058473 A CN 201080058473A CN 102665406 A CN102665406 A CN 102665406A
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CN102665406B (en
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阿列克谢·格里德涅夫
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Saudi Aramco Technologies Co
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Novomer Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/02—Guanidine; Salts, complexes or addition compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms

Abstract

The present invention provides methods for the synthesis of polycyclic guanidine compounds. In certain embodiments, provided methods include the step of contacting a described reagent with a triamine compound to provide a polycyclic guanidine compound.

Description

The method of synthetic many ring guanidine compounds
The cross reference of related application
The application's case is advocated the U.S. Provisional Application case the 61/290th of application on December 24th, 2009; The U.S. Provisional Application case the 61/299th of application on January 28th, No. 087 1; The U.S. Provisional Application case the 61/422nd of No. 047 and on December 13rd, 2010 application; No. 492 priority, the mode that said application case is quoted separately in full is incorporated herein.
Technical field
Background technology
Strong basicity bicyclo guanidine and three ring guanidine compounds have been used for organic synthesis and polymeric additive field.Regrettably, the method for current synthetic these compounds produces has toxic byproduct (for example hydrogen sulphide) or needs extremely exacting terms.
Through using triamine and reagent (CS for example 2Or dialkyl carbonate) prepare bicyclo guanidine, for example 1,5,7-three azabicyclos [5.5.0] last of the ten Heavenly stems-5-alkene (TBD).United States Patent (USP) the 4th, 797 has been described CS No. 487 2Approach.This approach has the benefit of using cheap initial substance and high yield being provided.Yet it produces the compound hydrogen sulphide (H of poisonous in a large number and stench simultaneously 2S) as byproduct of reaction.H 2The generation of S needs extra safety precaution and uses expensive washer to prevent that it is discharged in the environment.
The open case 2009/0281314 of United States Patent (USP) has been described a kind of fresh approach with the open case WO2009/137728 of PCT.Wherein disclosed approach uses the ring urea as a kind of carbon source.Owing to do not produce H 2S is so this approach compares CS 2Approach improves to some extent; Yet chemical process needs multistep processes and harsh reaction condition.
Therefore, still need cost-effective cheap approach for many rings guanidine (for example TBD).
Summary of the invention
In one aspect, the present invention provides a kind of facilitated method of synthetic many ring guanidine compounds.In certain embodiments, syntheticly comprise that said reagent is contacted with triamine compound obtains the steps of encircling guanidine compounds more.As defined herein, said reagent comprises guanidine, non-annularity guanidine, cyanamide, cyanogen imines, melamine and melamine derivative.
In certain embodiments, the present invention is contained from guanidine or more in general from the synthetic methods of encircling guanidines of non-annularity guanidine more.In certain embodiments, method comprises that the non-annularity guanidine is contacted with triamine obtains the steps of encircling guanidine compounds more, as following
Shown in the flow process 1:
Figure BDA00001794363300021
Flow process 1
Wherein variable and R group are as described herein.
In certain embodiments, the present invention is contained from cyanamide or more in general from the synthetic methods of encircling guanidines of cyanogen imines more.In certain embodiments, method comprises that the cyanogen imines is contacted with triamine obtains the steps of encircling guanidine compounds more, shown in following flow process 2:
Figure BDA00001794363300022
Flow process 2
Wherein variable and R group are as described herein.
In certain embodiments, the method from the synthetic many ring guanidines of melamine or derivatives thereof is contained in the present invention.In certain embodiments, method comprises that melamine or melamine derivative are contacted with triamine obtains the steps of encircling guanidine compounds more, shown in following flow process 3:
Flow process 3
Wherein variable and R group are as described herein.
Description of drawings
Fig. 1 describes to use thick TBD product that the inventive method produces 1H NMR spectrum.
Embodiment
Definition
The definition of the particular functional group and the technical terms of chemistry is below described in more detail.For purposes of the present invention; Chemical element is according to the periodic table of elements (Periodic Table of the Elements); The CAS version, chemistry and physics handbook (Handbook of Chemistry and Physics), the 75th edition; Inside front cover is differentiated, and the particular functional group is general as wherein said the definition.In addition; Vitochemical General Principle and particular functional part and reactivity are described in organic chemistry (Organic Chemistry), Thomas's Soret that (Thomas Sorrell), the textbook of studying science greatly (University Science Books); Suo Salituo (Sausalito), 1999; Smith (Smith) and horse strange (March), the Advanced Organic Chemistry (March ' s Advanced Organic Chemistry) that horse is strange, the 5th edition, John Wei Li publishing company (John Wiley Sons, Inc.), New York (New York), 2001; La Roque (Larock), comprehensive organic transformation (Comprehensive Organic Transformations), company of VCH publishing house (VCH Publishers, Inc.), New York (New York), 1989; Ka Lusesi (Carruthers), some modern methodology of organic synthesis (Some Modern Methods of Organic Synthesis), the 3rd edition, Cambridge University Press (Cambridge University Press), Cambridge (Cambridge), 1987; Its full content separately is incorporated herein by reference.
Some compound of the present invention can comprise one or more asymmetric centers, and therefore can various stereoisomeric forms in any ratio exist, for example enantiomter and/or diastereoisomer.Therefore, The compounds of this invention can be indivedual enantiomters, diastereoisomer or geometric isomer form with its composition, maybe can be the stereoisomer mixture form.In certain embodiments, The compounds of this invention is the mapping pure compound.In some other embodiment, the mixture of enantiomter or diastereoisomer is provided.
In addition, only if indicate in addition, otherwise as described herein, some compound can have one or more pairs key, thereby can Z or the existence of E isomeric forms.The compound that is the individual isomers form that does not contain other isomer in fact or is various mixture of isomers (the for example racemic mixture of enantiomter) form is contained in the present invention in addition.Except that above-claimed cpd itself, the present invention is also contained and is comprised one or more compound compositions.
As used herein, term " isomer " comprises any and all geometric isomers and stereoisomer.For instance, " isomer " comprise cis and transisomer, E and Z isomer, R and S enantiomter, diastereoisomer, (D)-isomer, (L)-isomer, its racemic mixture with and other mixture, all within the scope of the invention.For instance, in certain embodiments, compound can substantially not contain under the situation of one or more corresponding stereoisomers to be provided, and also can be described as " spatial chemistry enrichment ".
As used herein, term " halogen " and " halogen " are meant and are selected from fluorine (F), (Cl), bromine (Br) and iodine (atom I) for chlorine.
As used herein, term " aliphatic series " or " aliphatic group " expression can be straight chain (promptly not branch), branched chain or ring-type (comprise condense, bridging and spiro-condensed encircle) more and can saturatedly fully maybe can contain one or more unsaturated units but be not the hydrocarbon part of aromatics.Unless otherwise mentioned, otherwise aliphatic group contains 1 to 30 carbon atom.In certain embodiments, aliphatic group contains 1 to 12 carbon atom.In certain embodiments, aliphatic group contains 1 to 8 carbon atom.In certain embodiments, aliphatic group contains 1 to 6 carbon atom.In certain embodiments, aliphatic group contains 1 to 5 carbon atom, and in certain embodiments, aliphatic group contains 1 to 4 carbon atom, and in other embodiments, aliphatic group contains 1 to 3 carbon atom, and in other embodiments, aliphatic group contains 1 to 2 carbon atom.The aliphatic group that is fit to include, but is not limited to straight chain or branched chain alkyl, thiazolinyl and alkynyl with and heterozygote, for example (cycloalkyl) alkyl, (cycloalkenyl group) alkyl or (cycloalkyl) thiazolinyl.
As used herein; Term " heterolipid family " or " assorted aliphatic group " expression also have 1 to 5 heteroatomic choosing wantonly through substituted hydrocarbon part except that carbon atom; It can be straight chain (promptly not branch), branched chain or ring-type (" heterocycle shape ") and can saturatedly fully maybe can contain one or more unsaturated units, but it is not an aromatics.Term " hetero atom " is meant nitrogen, oxygen or sulphur and comprises nitrogen or any quaternized form of any oxidised form of sulphur and basic nitrogen.Term " nitrogen " also comprises through substituted nitrogen.Unless otherwise mentioned, otherwise assorted aliphatic group contains 1 to 6 carbon atom, and wherein 1 to 3 carbon atom is optional and be selected from the hetero atom displacement of oxygen, nitrogen and sulphur independently.In certain embodiments, assorted aliphatic group contains 1 to 4 carbon atom, and wherein 1 to 2 carbon atom is optional and be selected from the hetero atom displacement of oxygen, nitrogen and sulphur independently.In other embodiments, assorted aliphatic group contains 1 to 3 carbon atom, and wherein 1 carbon atom is optional and be selected from the hetero atom displacement of oxygen, nitrogen and sulphur independently.The assorted aliphatic group that is fit to includes, but is not limited to straight chain or the assorted alkyl of branched chain, assorted thiazolinyl and assorted alkynyl.
As used herein, term " unsaturated " means the part with one or more pairs key or triple bond.
As described herein; The term " cyclic aliphatic " or " carbocyclic ring " that use separately or use as the part of major part are meant the unsaturated monocycle of saturated or part, dicyclo or the multi-loop system with 3 to 20 members, and wherein aliphatic loop systems is like preceding text institute's definition and optional warp replacement described herein.The cyclic aliphatic base is including but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, suberyl, cycloheptenyl, ring octyl group, cyclo-octene base, dicyclo [2.2.1] heptyl, norborny (norbornyl), spiral shell [4.5] decyl and cyclo-octadiene base.In certain embodiments, cycloalkyl has 3 to 6 carbon.Term " cyclic aliphatic " or " carbocyclic ring " also comprise the aliphatic series ring that is fused to one or more aromatics or non-aromatic ring, for example decahydro naphthyl or tetralyl, and wherein linking group or tie point are positioned on the aliphatic series ring.In certain embodiments, carbocylic radical is a bicyclic carbocyclic group.In certain embodiments, carbocylic radical is three ring carbocylic radicals.In certain embodiments, carbocylic radical is many ring carbocylic radicals.In certain embodiments, term " 3 to 14 yuan of carbocyclic rings " and " C 3-14Carbocyclic ring " be meant 3 to 8 yuan of saturated or unsaturated monocycle carbocyclic rings of part or 7 to 14 yuan of saturated or unsaturated many ring carbocyclic rings of part.
As used herein, term " alkyl " is meant through removing straight chain or the branched chain saturated hydrocarbon group that single hydrogen atom is derived Zi the aliphatic series part that contains 1 to 6 carbon atom.Unless otherwise mentioned, otherwise alkyl contains 1 to 12 carbon atom.In certain embodiments, alkyl contains 1 to 8 carbon atom.In certain embodiments, alkyl contains 1 to 6 carbon atom.In certain embodiments, alkyl contains 1 to 5 carbon atom.In certain embodiments, alkyl contains 1 to 4 carbon atom.In certain embodiments, alkyl contains 1 to 3 carbon atom.In certain embodiments, alkyl contains 1 to 2 carbon atom.The instance of alkyl includes, but is not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, sec-amyl, isopentyl, the tert-butyl group, n-pentyl, neopentyl, n-hexyl, Sec-Hexyl, n-heptyl, n-octyl, positive decyl, n-undecane base, dodecyl etc.
As used herein, term " thiazolinyl " expression is through removing single hydrogen atom from straight chain with at least one carbon-carbon double bond or the aliphatic monoradical of partly deriving of branched chain.Unless otherwise mentioned, otherwise thiazolinyl contains 2 to 12 carbon atoms.In certain embodiments, thiazolinyl contains 2 to 8 carbon atoms.In certain embodiments, thiazolinyl contains 2 to 6 carbon atoms.In certain embodiments, thiazolinyl contains 2 to 5 carbon atoms.In certain embodiments, thiazolinyl contains 2 to 4 carbon atoms.In certain embodiments, thiazolinyl contains 2 to 3 carbon atoms.In certain embodiments, thiazolinyl contains 2 carbon atoms.Thiazolinyl comprises for example vinyl, acrylic, cyclobutenyl, 1-methyl-2-butene-1-base etc.
As used herein, term " alkynyl " is meant through removing single hydrogen atom from straight chain with at least one carbon carbon triple bond or the aliphatic monoradical of partly deriving of branched chain.Unless otherwise mentioned, otherwise alkynyl contains 2 to 12 carbon atoms.In certain embodiments, alkynyl contains 2 to 8 carbon atoms.In certain embodiments, alkynyl contains 2 to 6 carbon atoms.In certain embodiments, alkynyl contains 2 to 5 carbon atoms, and in certain embodiments, alkynyl contains 2 to 4 carbon atoms, and in other embodiments, alkynyl contains 2 to 3 carbon atoms, and in other embodiments, alkynyl contains 2 carbon atoms.Representative alkynyl includes, but is not limited to acetenyl, 2-propynyl (propargyl), 1-propinyl etc.
Term " aryl " use separately or as " aralkyl ", " aralkoxy " or " aryloxy alkyl " in be meant to have monocycle and the multi-loop system that amounts to 5 to 20 ring memberses when using as the part of major part, wherein at least one ring in the system be aromatic ring and wherein each ring in the system contain 3 to 12 ring memberses.Term " aryl " can exchange with term " aryl rings " and use.In certain embodiments of the present invention, " aryl " is meant aromatic ring system, and it includes, but is not limited to phenyl, xenyl, naphthyl, anthryl etc., and it can have one or more substituting groups.As used herein, comprise also in the scope of term " aryl " that aromatic ring is fused to the group of one or more other rings, for example benzofuranyl, indanyl, phthalimide-based, naphthalimide, phenanthridinyl or tetralyl etc.In certain embodiments, term " 6 to 10 yuan of aryl " and " C 6-10Aryl " be meant phenyl or 8 to 10 yuan of polyaromatic rings.In certain embodiments, term " 6 to 14 yuan of aryl " and " C 6-14Aryl " be meant phenyl or 8 to 14 yuan of polyaromatic rings.
(for example " heteroarylalkyl " or " aralkoxy of mixing ") is meant to have 5 to 14 annular atomses (preferably having 5,6 or 9 annular atomses), have 6,10 or 14 pi-electrons shared in annular array and except that carbon atom, also have 1 to 5 heteroatomic group to the term " heteroaryl " that uses separately or use as the part of major part with " assorted virtue-".Term " hetero atom " is meant nitrogen, oxygen or sulphur and comprises nitrogen or any quaternized form of any oxidised form of sulphur and basic nitrogen.Heteroaryl includes, but is not limited to thienyl, furyl, pyrrole radicals, imidazole radicals, pyrazolyl, triazolyl, tetrazole radical 、 oxazolyl 、 isoxazolyl 、 oxadiazole base, thiazolyl, isothiazolyl, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, indolizine base, purine radicals, naphthyridines base, benzofuranyl and pteridyl.As used herein, term " heteroaryl " and " assorted virtue-" comprise that also heteroaromatic rings is fused to the group of one or more aryl rings, cyclic aliphatic ring or heterocyclic ring, and wherein linking group or tie point are positioned on the heteroaromatic rings.Limiting examples comprises indyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuran group, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolines base, phthalazinyl, quinazolyl, quinoxalinyl, 4H-quinolizine base, carbazyl, acridinyl, phenazinyl, phenothiazinyl 、 phenoxazine group, tetrahydric quinoline group, tetrahydro isoquinolyl and pyrido [2; 3-b]-1,4-oxazine-3 (4H)-ketone.Heteroaryl can be bicyclic heteroaryl or bicyclic heteroaryl.Term " heteroaryl " can exchange with term " heteroaryl ring " or " heteroaromatic base " and use, and any of these term all comprises optional through substituted ring.Term " heteroarylalkyl " is meant that through the substituted alkyl of heteroaryl wherein alkyl and heteroaryl moieties are optional independently through replacing.Term " heteroarylalkyl " is meant that through the substituted alkyl of heteroaryl wherein alkyl and heteroaryl moieties are optional independently through replacing.In certain embodiments, term " 5 to 10 yuan of heteroaryls " is meant to have 1 to 3 heteroatomic 5 to 6 yuan of heteroaryl ring that are independently selected from nitrogen, oxygen or sulphur, or has 1 to 4 heteroatomic 8 to 10 yuan of bicyclic heteroaryl ring that are independently selected from nitrogen, oxygen or sulphur.In certain embodiments, term " 5 to 14 yuan of heteroaryls " is meant to have 1 to 3 heteroatomic 5 to 6 yuan of heteroaryl ring that are independently selected from nitrogen, oxygen or sulphur, or has 1 to 4 heteroatomic 8 to 14 yuan of polyheteroaromatic ring that are independently selected from nitrogen, oxygen or sulphur.
As used herein; Term " heterocycle ", " heterocyclic radical ", " heterocyclic group " and " assorted cyclic rings " interchangeable use, and be meant saturated or part is unsaturated and except that carbon atom, also have one or more (preferably having 1 to 4) heteroatomic 3 to 7 yuan of monocyclic heterocycles parts or 7 to 14 yuan of bicyclic heterocycle parts stablized like the preceding text definition.When the annular atoms about heterocycle used, term " nitrogen " comprised through substituted nitrogen.For instance, be selected from the heteroatomic saturated of oxygen, sulphur or nitrogen or the unsaturated ring of part having 0 to 3, nitrogen can be N (as 3, in the 4-dihydro-2 h-pyrrole base), NH (as in pyrrolidinyl) or +NR (as at N-in substituted pyrrolidinyl).In certain embodiments, term " 3 to 7 yuan of heterocycles " is meant and has 1 to 2 heteroatomic 3 to 7 yuan of saturated or unsaturated monocyclic heterocycles shape of part ring that are independently selected from nitrogen, oxygen or sulphur.In certain embodiments, term " 3 to 8 yuan of heterocycles " is meant and has 1 to 2 heteroatomic 3 to 8 yuan of saturated or unsaturated monocyclic heterocycles shape of part ring that are independently selected from nitrogen, oxygen or sulphur.In certain embodiments; Term " 3 to 12 yuan of heterocycles " is meant to have 1 to 2 heteroatomic 3 to 8 yuan of saturated or unsaturated monocyclic heterocycles shape of part ring that are independently selected from nitrogen, oxygen or sulphur, or has 1 to 3 heteroatomic 7 to 12 yuan of saturated or assorted cyclic rings of the unsaturated many rings of part that are independently selected from nitrogen, oxygen or sulphur.In certain embodiments; Term " 3 to 14 yuan of heterocycles " is meant to have 1 to 2 heteroatomic 3 to 8 yuan of saturated or unsaturated monocyclic heterocycles shape of part ring that are independently selected from nitrogen, oxygen or sulphur, or has 1 to 3 heteroatomic 7 to 14 yuan of saturated or assorted cyclic rings of the unsaturated many rings of part that are independently selected from nitrogen, oxygen or sulphur.
Assorted cyclic rings can any hetero atom or carbon atom be connected to its side group, thereby produce rock-steady structure and any annular atoms all can be chosen wantonly through replacing.Said instance saturated or part unsaturated heterocycle base is including but not limited to tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, pyrrolidone-base, piperidyl, pyrrolinyl, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, oxazole alkyl, piperazinyl, alkyl dioxin, dioxolanyl, diazepine base, oxygen azatropylidene base, sulphur azatropylidene base, morpholinyl and quininuclidinyl.Term " heterocycle ", " heterocyclic radical ", " heterocyclic ring ", " heterocyclic group " and " heterocyclic moiety " interchangeable in this article use; And comprise that also heterocyclic ring is fused to the group of one or more aryl rings, heteroaryl ring or cyclic aliphatic ring; For example indoline base, 3H-indyl, Chromanyl, phenanthridinyl or tetrahydric quinoline group, wherein linking group or tie point are positioned on the heterocyclic ring.Heterocyclic radical can be monocyclic heterocycles base or bicyclic heterocyclic radical.Term " heterocyclic radical alkyl " is meant that through the substituted alkyl of heterocyclic radical wherein alkyl and heterocyclic radical part is optional independently through replacing.
As used herein, term " part is unsaturated " is meant the loop section that comprises at least one two key or triple bond.Term " part is unsaturated " plans to contain the ring with a plurality of unsaturated sites, but does not plan to comprise like aryl defined herein or heteroaryl moieties.
As described herein, The compounds of this invention can contain " optional through substituted " part.In general, no matter whether the front has term " randomly " to term " through replacing ", all means the substituting group displacement of one or more hydrogen through being fit to of specified part.Only if indicate in addition; Otherwise " optional through substituted " group can have suitable substituting group in each instead position of group; And when an above position in any both fixed structures can replace through the substituting group that is selected from designated group more than, the substituting group of each position can be identical or different.The substituent combination of the present invention's anticipation preferably can form stable or chemically feasible combination of compounds.As used herein, term " is stablized " and is meant that compound standing to allow its manufacturing, detection and in certain embodiments, when allowing its recovery, purifying and being used for the condition of one or more purposes disclosed herein, does not change in fact.
In some chemical constitutions in this article, demonstrate substituting group and be connected to across the chain of said molecule or the key of the key in the ring.Should be understood that this shows that one or more substituting groups can be connected to any available position of ring or chain (substituting the hydrogen atom of parent structure usually).Have under the situation of two instead positions at the atom through substituted ring or chain like this, two groups can be present on the same annular atoms.Only if indicate in addition, otherwise when having an above substituting group, each substituting group is independently to define with respect to other substituting group, and each substituting group can have various structure.Shown in across the substituting group of key of ring be-situation of R under, its implication with " choose wantonly " described in said ring such as the earlier paragraphs through substituted identical.
Suitable unit price substituting group on the substitutable carbon atom of " optional through substituted " group is halogen independently;-(CH 2) 0-4R o-(CH 2) 0-4OR o-O-(CH 2) 0-4C (O) OR o-(CH 2) 0-4CH (OR o) 2-(CH 2) 0-4SR o-(CH 2) 0-4Ph, it can be through R oReplace;-(CH 2) 0-4O (CH 2) 0-1Ph, it can be through R oReplace;-CH=CHPh,, it can be through R oReplace;-NO 2-CN;-N 3-(CH 2) 0-4N (R o) 2-(CH 2) 0-4N +(R o) 3,-(CH 2) 0-4N (R o) C (O) R o-N (R o) C (S) R o-(CH 2) 0-4N (R o) C (O) NR o 2-N (R o) C (S) NR o 2-(CH 2) 0-4N (R o) C (O) OR o-N (R o) N (R o) C (O) R oN (R o) N (R o) C (O) NR o 2-N (R o) N (R o) C (O) OR o-(CH 2) 0-4C (O) R o-C (S) R o-(CH 2) 0-4C (O) OR o-(CH 2) 0-4C (O) N (R o) 2-(CH 2) 0-4C (O) SR o-(CH 2) 0-4C (O) OSiR o 3-(CH 2) 0-4OC (O) R o-OC (O) (CH 2) 0-4SR-, SC (S) SR o-(CH 2) 0-4SC (O) R o-(CH 2) 0-4C (O) NR o 2-C (S) NR o 2-C (S) SR o-SC (S) SR o,-(CH 2) 0-4OC (O) NR o 2-C (O) N (OR o) R o-C (O) C (O) R o-C (O) CH 2C (O) R o-C (NOR o) R o-(CH 2) 0-4S SR o-(CH 2) 0-4S (O) 2R o-(CH 2) 0-4S (O) 2OR o-(CH 2) 0-4OS (O) 2R o-S (O) 2NR o 2-(CH 2) 0-4S (O) R o-N (R o) S (O) 2NR o 2-N (R o) S (O) 2R o-N (OR o) R o-C (NH) NR o 2-P (O) 2R o-P (O) R o 2-OP (O) R o 2-OP (O) (OR o) 2SiR o 3-(C 1-4Straight chain or branched chain alkylidene) O-N (R o) 2Or-(C 1-4Straight chain or branched chain alkylidene) C (O) O-N (R o) 2, each R wherein oCan be like following definition through replacing and being hydrogen, C independently 1-8Aliphatic group ,-CH 2Ph ,-O (CH 2) 0-1Ph or have 0 to 4 heteroatomic 5 to 6 yuan of saturated rings, the unsaturated ring of part or aryl rings that is independently selected from nitrogen, oxygen or sulphur, although above definition is perhaps arranged, two independent R that occur oTogether with its get involved atom form have 0 to 4 be independently selected from nitrogen, oxygen or sulphur heteroatomic 3 to 12 yuan saturated, part is unsaturated or aryl monocycle or many rings, it can be like the definition warp replacement of following institute.
R o(or by two independent R that occur oGet involved the ring that atom forms together with it) on suitable unit price substituting group independently for halogen ,-(CH 2) 0-2R ,-(halogen R ) ,-(CH 2) 0-2OH ,-(CH 2) 0-2OR ,-(CH 2) 0-2CH (OR ) 2-O (halogen R ) ,-CN ,-N 3,-(CH 2) 0-2C (O) R ,-(CH 2) 0-2C (O) OH ,-(CH 2) 0-2C (O) OR ,-(CH 2) 0-4C (O) N (R o) 2-(CH 2) 0-2SR ,-(CH 2) 0-2SH ,-(CH 2) 0-2NH 2,-(CH 2) 0-2NHR ,-(CH 2) 0-2NR 2,-NO 2,-SiR 3,-OSiR 3,-C (O) SR ,-(C 1-4Straight chain or branched chain alkylidene) C (O) OR Or-SSR , each R wherein Without replace or when preposition " halogen " only through one or more halogens replacements, and be independently selected from C 1-4Aliphatic group ,-CH 2Ph ,-O (CH 2) 0-1Ph or have 0 to 4 heteroatomic 5 to 6 yuan of saturated rings, the unsaturated ring of part or aryl rings that is independently selected from nitrogen, oxygen or sulphur.R oThe divalent substituent that is fit on the saturated carbon atom comprises=O and=S.
Suitable divalent substituent on the saturated carbon atom of " optional through substituted " group comprises following :=O ,=S ,=NNR * 2,=NNHC (O) R *,=NNHC (O) OR *,=NNHS (O) 2R *,=NR *,=NOR *,-O (C (R * 2)) 2-3O-or-S (C (R * 2)) 2-3S-, wherein each R that independently occurs *Be be selected from hydrogen, can be like following definition through substituted C 1-6Aliphatic group or have 0 to 4 and be independently selected from the heteroatomic of nitrogen, oxygen or sulphur without substituted 5 to 6 yuan of saturated rings, the unsaturated ring of part or aryl rings.The suitable divalent substituent that is attached to the ortho position substitutable carbon of " optional through substituted " group comprises :-O (CR * 2) 2-3O-, wherein each R that independently occurs *Be be selected from hydrogen, can be like following definition through substituted C 1-6Aliphatic group or have 0 to 4 and be independently selected from the heteroatomic of nitrogen, oxygen or sulphur without substituted 5 to 6 yuan of saturated rings, the unsaturated ring of part or aryl rings.
R *Aliphatic group on suitable substituting group comprise halogen ,-R ,-(halogen R ) ,-OH ,-OR ,-O (halogen R ) ,-CN ,-C (O) OH ,-C (O) OR ,-NH 2,-NHR ,-NR 2Or-NO 2, each R wherein Without replace or when preposition " halogen " only through one or more halogens replacements, and be C independently 1-4Aliphatic group ,-CH 2Ph ,-O (CH 2) 0-1Ph or have 0 to 4 heteroatomic 5 to 6 yuan of saturated rings, the unsaturated ring of part or aryl rings that is independently selected from nitrogen, oxygen or sulphur.
Suitable substituting group on the instead nitrogen of " optional through substituted " group comprises
Figure BDA00001794363300091
Or
Figure BDA00001794363300093
Wherein respectively Independently by hydrogen, can be defined through substituted C as following 1-6Aliphatic group, without substituted-OPh or have 0 to 4 and be independently selected from the heteroatomic of nitrogen, oxygen or sulphur without substituted 5 to 6 yuan of saturated rings, the unsaturated ring of part or aryl rings, although above definition is perhaps arranged, two independent occurs
Figure BDA00001794363300095
Together with its get involved atom form have 0 to 4 be independently selected from nitrogen, oxygen or sulphur heteroatomic without substituted 3 to 12 yuan saturated, part is unsaturated or aryl monocycle or many rings.Can be replaced by nitrogen can be 3
Figure BDA00001794363300096
substituents to give a charged ammonium moieties
Figure BDA00001794363300097
where ammonium moieties further with a suitable counter-ion complexation.
Figure BDA00001794363300098
Aliphatic group on suitable substituting group be independently halogen ,-R ,-(halogen R ) ,-OH ,-OR ,-O (halogen R ) ,-CN ,-C (O) OH ,-C (O) OR ,-NH 2,-NHR ,-NR 2Or-NO 2, each R wherein Without replace or when preposition " halogen " only through one or more halogens replacements, and be C independently 1-4Aliphatic group ,-CH 2Ph ,-O (CH 2) 0-1Ph or have 0 to 4 heteroatomic 5 to 6 yuan of saturated rings, the unsaturated ring of part or aryl rings that is independently selected from nitrogen, oxygen or sulphur.
As used herein, phrase " said reagent " comprises the compound that can obtain many ring guanidine compounds with triamine.The said compound of exemplary includes, but is not limited to guanidine, non-annularity guanidine, cyanamide, cyanogen imines, melamine and melamine derivative.The salt form of above mentioned compound also contained in phrase " said reagent ".Through limiting examples, the salt form of guanidine can comprise guanidine carbonate, guanidine sulfate, guanidine acetate, guanidine nitrate, p-methyl benzenesulfonic acid guanidine, guanidine hydrochloride, phosphoguanidine etc.
The present invention provides the method for the many rings of preparation guanidine compound.In certain embodiments, the method that is provided comprises the step that said reagent is contacted with triamine compound.
In certain embodiments, the present invention is contained from guanidine or more in general from the synthetic methods of encircling guanidines of non-annularity guanidine more.In certain embodiments, method comprises that the non-annularity guanidine is contacted with triamine obtains the steps of encircling guanidine compounds more, shown in following flow process 1:
Flow process 1
Wherein variable and R group are as described herein.In certain embodiments, each R bBe hydrogen.
In certain embodiments, method comprises that the non-annularity guanidine is contacted with triamine obtains the steps of encircling guanidine compounds more, shown in following flow process 1a:
Figure BDA00001794363300102
Flow process 1a
Wherein variable is as described herein with other R group.In certain embodiments, each R bBe hydrogen.
In certain embodiments, method comprises that the non-annularity guanidine is contacted with triamine obtains the steps of encircling guanidine compounds more, shown in following flow process 1b:
Figure BDA00001794363300103
Flow process 1b
Wherein variable is as described herein with other R group.In certain embodiments, each R bBe hydrogen.
In certain embodiments, the present invention is contained from cyanamide or more in general from the synthetic methods of encircling guanidines of cyanogen imines more.In certain embodiments, method comprises that the cyanogen imines is contacted with triamine obtains the steps of encircling guanidine compounds more, shown in following flow process 2:
Figure BDA00001794363300104
Flow process 2
Wherein variable and R group are as described herein.In certain embodiments, each R bBe hydrogen.In certain embodiments, R is hydrogen or alkyl when occurring at every turn.
In certain embodiments, method comprises that the cyanogen imines is contacted with triamine obtains the steps of encircling guanidine compounds more, shown in following flow process 2a:
Figure BDA00001794363300111
Flow process 2a
Wherein variable is as described herein with other R group.In certain embodiments, each R bBe hydrogen.
In certain embodiments, the method from the synthetic many ring guanidines of melamine or derivatives thereof is contained in the present invention.In certain embodiments, method comprises that melamine or melamine derivative are contacted with triamine obtains the steps of encircling guanidine compounds more, shown in following flow process 3:
Figure BDA00001794363300112
Flow process 3
Wherein variable is as described herein with other R group.In certain embodiments, each R xAnd R yBe hydrogen.In certain embodiments, R xAnd R yWhen occurring, be hydrogen or alkyl independently at every turn.
In certain embodiments, method comprises that melamine or melamine derivative are contacted with triamine obtains the steps of encircling guanidine compounds more, shown in following flow process 3a:
Figure BDA00001794363300113
Flow process 3a
Wherein variable is as described herein with other R group.In certain embodiments, each R xAnd R yBe hydrogen.
In certain embodiments, the method that is provided comprises makes said reagent contact in the presence of promoter with triamine.
In certain embodiments, promoter is acid.The acid that is fit to can include, but is not limited to inorganic acid (for example hydrochloric acid, sulfuric acid or phosphoric acid) and organic acid (for example sulfonic acid).The sulfonic acid that is fit to comprises alkyl sulfonic acid or aryl sulfonic acid, is wherein known by the skilled craftsman in a large number.Exemplary sulfonic acid includes, but is not limited to Loprazolam, trifluoromethayl sulfonic acid and p-methyl benzenesulfonic acid.In certain embodiments, sour promoter can comprise solid supported acid.Solid supported acid can comprise sour exchanger resin (for example sulfonate resin, for example Dowex TMAnd Amberlyst TMResin) and load on well-known other solid supported acid in acid and/or this technology on the inorganic matrix (for example silica or aluminium oxide).
In certain embodiments, promoter is alkali.In certain embodiments, promoter is highly basic.The alkali that is fit to can include, but is not limited to one or more metal hydroxides or alkoxide.In certain embodiments, use one or more alkoxide of I family or II family metal.In certain embodiments, use sodium alkoxide, for example sodium methoxide, caustic alcohol, sodium isopropylate, sodium tert-butoxide etc.In certain embodiments, use lithium alkoxide, for example lithium methoxide, lithium ethoxide, isopropyl alcohol lithium, tert-butyl alcohol lithium etc.In certain embodiments, use potassium alcoholate, for example potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide etc.
Reagent
In certain embodiments, be suitable for the non-annularity guanidine that said reagent that the triamine compound in the inventive method uses can comprise guanidine or more in general comprise formula I:
Figure BDA00001794363300121
R wherein bWhen occurring, be independently selected from the group that forms by following: hydrogen, optional through substituted C at every turn 1-20Aliphatic group, optional through substituted aryl and nitrile.In certain embodiments, as described herein, the non-annularity guanidine of formula I exists with salt or adduct form.
In certain embodiments, R bBe that hydrogen and reagent are guanidine when occurring at every turn.In certain embodiments, R bIt when occurring hydrogen or alkyl at every turn.In certain embodiments, said non-annularity guanidine of the present invention is the tetraalkyl guanidine.In certain embodiments, said non-annularity guanidine of the present invention is a TMG.
In certain embodiments, R bWhen once occurring nitrile (C ≡ N).In certain embodiments, R bBe nitrile when once occurring and be hydrogen or alkyl when other time occurs at all.In certain embodiments, the said non-annularity guanidine of formula I is the dicyandiamide or derivatives thereofs.
In certain embodiments, be suitable for the cyanogen imines that said reagent that the triamine compound in the inventive method uses can comprise cyanamide or more in general comprise formula II:
Figure BDA00001794363300131
R wherein bWhen occurring, be independently selected from the group that forms by following at every turn:
Hydrogen, optional through substituted C 1-20Aliphatic group and optional through substituted aryl.In certain embodiments, the cyanogen imines of formula II exists with salt or adduct form.
In certain embodiments, each R bFor hydrogen and reagent are cyanamide.In certain embodiments, R bIt when occurring hydrogen or alkyl at every turn.
In certain embodiments, be suitable for the melamine derivative that said reagent that the triamine compound in the inventive method uses can comprise melamine or formula III:
R wherein xAnd R yWhen occurring, be independently selected from the group that forms by following: hydrogen, optional through substituted C at every turn 1-20Aliphatic group and optional through substituted aryl.In certain embodiments, the melamine derivative of formula III exists with salt or adduct form.
In certain embodiments, R xAnd R yBe that hydrogen and reagent are melamine when occurring at every turn.In certain embodiments, R xAnd R yIt when occurring hydrogen or alkyl at every turn.
In certain embodiments, the salt of said reagent or adduct can be used in the inventive method.In certain embodiments, the salt of said reagent or adduct comprise the non-annularity guanidine.In certain embodiments, the salt of said reagent or adduct comprise guanidine.In certain embodiments, the inventive method is used guanidinesalt, for example guanidine carbonate, guanidine sulfate, guanidine acetate, guanidine nitrate, p-methyl benzenesulfonic acid guanidine, guanidine hydrochloride, phosphoguanidine etc.In certain embodiments, the salt of said reagent or adduct comprise the cyanogen imines.In certain embodiments, the salt of said reagent or adduct comprise cyanamide.In certain embodiments, the salt of said reagent or adduct comprise melamine derivative.In certain embodiments, the salt of said reagent or adduct comprise melamine.
Triamine
In certain embodiments, used triamine has formula IV in the inventive method:
Figure BDA00001794363300141
Wherein:
R aBe to be selected from the group that forms by following: hydrogen, optional through substituted aliphatic group, optional through substituted assorted aliphatic group, optional through substituted aryl and optional through substituted heteroaryl;
R cBe optional existence the, wherein R cWhen occurring, be independently selected from the group that forms by following: halogen, optional through substituted aliphatic group, optional through substituted assorted aliphatic group, optional through substituted aryl and optional, wherein two or more R through substituted heteroaryl at every turn cGroup can be randomly forms one or more and optionally contains 1 to 3 and be selected from the heteroatomic optional through replacing ring of oxygen, nitrogen or sulphur together with getting involved atom;
N is the integer of 1 to 4 (comprising 1 and 4); And
M is the integer of 1 to 4 (comprising 1 and 4).
In certain embodiments, the method that is provided is used the triamine of formula IV:
Figure BDA00001794363300142
R wherein a, n and m such as preceding text definition.
In certain embodiments, triamine is optional through substituted two (aminopropyl) amine.In certain embodiments, triamine is optional through substituted two (amino-ethyl) amine.In certain embodiments, triamine is optional through substituted 2, two (amino methyl) piperidines of 6-.In certain embodiments, triamine is optional through substituted 2, two (amino-ethyl) piperidines of 6-.In certain embodiments, triamine is optional through substituted 2, two (amino methyl) pyrrolidines of 5-.In certain embodiments, triamine is optional through substituted 2, two (amino-ethyl) pyrrolidines of 5-.In certain embodiments, triamine is optional through substituted N-(2-amino-ethyl)-1,3-propane diamine.In certain embodiments, triamine is optional through substituted N-(2-amino-ethyl)-1,4-butanediamine.In certain embodiments, triamine is optional through substituted N-(2-aminopropyl)-1,4-butanediamine.
In certain embodiments, triamine used according to the invention is to be selected from following any one that describe:
Figure BDA00001794363300151
In certain embodiments, triamine has following structure:
Figure BDA00001794363300162
In certain embodiments, triamine has following structure:
Figure BDA00001794363300163
In certain embodiments, triamine has following structure:
Figure BDA00001794363300164
Method
The inventive method can be carried out in the presence of solvent or carry out with the pure reagent mixture.The solvent that is fit to can comprise common organic solvent, for example hydrocarbon, ether, ester, nitrile, sulfoxide, acid amides, chlorohydrocarbon, and/or the mixture of two or more any above-mentioned solvent.In certain embodiments, method is carried out under the situation of not adding solvent.
In certain embodiments, method comprises the step of reacting by heating thing.In certain embodiments, reactant mixture is heated between about 40 ℃ and about 300 ℃.In certain embodiments, reactant mixture is heated between about 50 ℃ and about 250 ℃.In certain embodiments, reactant mixture is heated between about 80 ℃ and about 200 ℃.In certain embodiments, reactant mixture is heated between about 100 ℃ and about 180 ℃.In certain embodiments, reactant mixture is heated between about 110 ℃ and about 180 ℃.In certain embodiments, reactant mixture is heated between about 110 ℃ and about 170 ℃.In certain embodiments, reactant mixture is heated between about 120 ℃ and about 170 ℃.In certain embodiments, reactant mixture is heated between about 130 ℃ and about 170 ℃.In certain embodiments, reactant mixture is heated between about 130 ℃ and about 160 ℃.In certain embodiments, reactant mixture is heated between about 140 ℃ and about 170 ℃.In certain embodiments, reactant mixture is heated between about 140 ℃ and about 160 ℃.
Those skilled in the art will realize that scalable allow temperature that reaction carries out with the duration so that the maximization of the productive rate of required product makes the minimum and/or maximal efficiency ground use laboratory equipment of accessory substance.Based on teaching among this paper and disclosure, the skilled craftsman will be easy to show and be prone to know said modification and the adjusting to institute's rendering method, and the adjusting of these parameters can be the normal experiment content.Scope of the present invention approval and contain said modification especially.
Use in the embodiment of the invention of acid accelerator in the method that is provided, the many rings guanidine that is produced by the method that is provided can the hydrochlorate form exist.In certain embodiments, the inventive method comprises the step through the said hydrochlorate that neutralizes with the alkaline treatment product in addition.In certain embodiments, neutralization procedure comprises one or more highly basic of use.In certain embodiments, use one or more metal hydroxides or alkoxide.In certain embodiments, use the alkoxide of one or more I families or II family metal.In certain embodiments, use sodium alkoxide, for example sodium methoxide, caustic alcohol, sodium isopropylate, sodium tert-butoxide etc.In certain embodiments, use solid supported alkali and/or polymerization alkali.In certain embodiments, anion exchange resin can be used to neutralize and/or separate the product that utilizes the inventive method to produce.
In this technology, typically, under the situation that does not break away from the spirit or scope of the present invention, can change the ratio of reactant.Based on disclosure among this paper and teaching, the modification of reactant (for example triamine and said reagent) ratio is the normal experiment content to those of ordinary skill in the art.In certain embodiments, triamine and said reagent are to exist to the mol ratio in about 1:4 scope at about 4:1.In certain embodiments, it exists to the mol ratio of about 1:2 with about 2:1.In certain embodiments, these reactants exist with approximate equimolar amounts.In certain embodiments, to form the carbon atom number that provides approximate relevant can be guanidine with said reagent through selecting for the ratio of triamine and said reagent.For instance, be among the embodiment of guanidine derivatives at said reagent, can adopt the guanidine derivatives of about 1:1 and the ratio of triamine.Likewise, if said reagent is dicyandiamide (or derivatives thereof) or melamine (or melamine derivative), the ratio of so said reagent and triamine can be about 1:2 or about 1:3 respectively.
Likewise, can change the amount of promoter.In certain embodiments, promoter is to exist to the ratio of about 10:1 with respect to the about 1:10 of one or both other reactants.In certain embodiments, said reagent and triamine and sour promoter exist with about equimolar amounts.
In certain embodiments, the method for synthetic TBD is contained in the present invention, and it comprises the step that guanidine carbonate and two (3-aminopropyl) amine are contacted in the presence of sulfonic acid.In certain embodiments, this method is carried out under the situation of not adding solvent.In certain embodiments, with reaction mass heated between about 80 ℃ and about 180 ℃.In certain embodiments, the reaction heating is less than about 12 hours time.In certain embodiments, heating guanidine carbonate and two (3-aminopropyl) amine in the presence of Loprazolam.In certain embodiments, the mol ratio between guanidine carbonate, triamine and the sulfonic acid is about 1:1:1.
In certain embodiments, the method for synthetic TBD is contained in the present invention, and it comprises the step that TMG and two (3-aminopropyl) amine are contacted in the presence of sulfonic acid.In certain embodiments, this method is carried out under the situation of not adding solvent.In certain embodiments, with reaction mass heated between about 80 ℃ and about 180 ℃.In certain embodiments, the reaction heating is less than about 12 hours time.In certain embodiments, heating TMG and two (3-aminopropyl) amine in the presence of Loprazolam.In certain embodiments, the mol ratio between TMG, triamine and the sulfonic acid is about 1:1:1.
In certain embodiments, the method for synthetic TBD is contained in the present invention, and it comprises the step that melamine or derivatives thereof and two (3-aminopropyl) amine are contacted in the presence of sulfonic acid.In certain embodiments, this method is carried out under the situation of not adding solvent.In certain embodiments, with reaction mass heated between about 80 ℃ and about 180 ℃.In certain embodiments, the reaction heating is less than about 12 hours time.In certain embodiments, heating melamine or derivatives thereof and two (3-aminopropyl) amine in the presence of Loprazolam.In certain embodiments, the mol ratio between melamine, triamine and the sulfonic acid is about 1:1:1.In certain embodiments, the mol ratio between melamine, triamine and the sulfonic acid is about 1:2:2.In certain embodiments, the mol ratio between melamine, triamine and the sulfonic acid is about 1:3:3.
Instance
The non-restrictive illustrative of following instance as certain embodiments of the invention is provided.
Instance 1. uses the synthetic TBD mesylate of guanidine carbonate
1.9g Loprazolam (0.02mol) and 3.6g guanidine carbonate (0.02mol) are packed in the flask and put into 150 ℃ of baths.After 10 minutes, add two (3-aminopropyl) amine (0.02mol) of 2.6g.After 6 hours, make the reactant mixture cooling and use chloroform extraction.The evaporation chloroformic solution obtains the white solid piece that 1.1g contains the TBD mesylate. 1H?NMR(CDC1 3):8.39(s,2H),3.25(m,8H),2.72(s,3H),1.93(m,4H)。
Instance 2. uses the replacement scheme of the synthetic TBD mesylate of guanidine carbonate
4.5g guanidine carbonate (0.025mol) is packed in the flask, in flask, add 4.9g Loprazolam (0.05mol).Heating blends in 150 ℃ of oil baths.Heat after 5 minutes, add two (3-aminopropyl) amine (0.05mol) of 6.5g.After 2 hours, reaction mixture obtains white solid piece (13.9g).Use NMR, find that about 70% pair (3-aminopropyl) amine changes into the TBD mesylate.
Instance 3. uses the replacement scheme of the synthetic TBD mesylate of TMG
In the mixture of 1.16g TMG (0.01mol) and two (3-aminopropyl) amine (0.01mol) of 1.3g, add 0.98g Loprazolam (0.01mol), and put into 140 ℃ of baths.After 3 hours, make the reactant mixture cooling and use chloroform extraction.The evaporation chloroformic solution obtains the white solid piece.The NMR of crude product analyzes and shows that 79% pair of (3-aminopropyl) amine changes into the TBD mesylate.
Instance 4. uses the synthetic TBD hydrochloride of guanidine hydrochloride
Under nitrogen, 4.8g guanidine hydrochloride (0.05mol) and two (3-aminopropyl) amine (0.05mol) of 6.5g were being stirred 6 hours under 160 ℃.The proton N MR spectrum (referring to Fig. 1) of crude product shows that 80% pair of (3-aminopropyl) amine changes into the TBD hydrochloride.
Instance 5. uses the synthetic TBD carbonate of guanidine carbonate
Under nitrogen, 2.76g guanidine carbonate (0.012mol) and two (3-aminopropyl) amine (0.025mol) of 3.25g were being stirred 6 hours under 160 ℃.The proton N MR spectrum of crude product shows that about 60% pair (3-aminopropyl) amine changes into TBD carbonate.
Instance 6. uses the replacement scheme of the synthetic TBD mesylate of dicyandiamide
In the mixture of 4.2g dicyandiamide (0.05mol) and two (3-aminopropyl) amine (0.01mol) of 1.3g, add 0.98g Loprazolam (0.01mol), and put into 160 ℃ of baths lasting 6 hours.The proton N MR spectrum of crude product shows that 88% pair of (3-aminopropyl) amine changes into the TBD mesylate.
Instance 7. uses the replacement scheme of the synthetic TBD mesylate of cyanamide
In the mixture of 0.84g cyanamide (0.02mol) and two (3-aminopropyl) amine (0.02mol) of 2.6g, slowly add 1.9g Loprazolam (0.02mol).Reactant mixture was kept under 150 ℃ 5 hours.The proton N MR spectrum of crude product shows that about 83% pair (3-aminopropyl) amine changes into the TBD mesylate.
Instance 8. separates TBD
The TBD mesylate can come purifying through being dissolved in the chloroform.Can obtain free TBD through potassium methoxide or the sodium methoxide that in the methanol solution of TBD mesylate, adds equimolar amounts.Also can use method known in this technology from other TBD salt, to separate TBD.
Instance 9. uses guanidine hydrochloride Synthetic 2,3,5,6-tetrahydrochysene-1H-imidazo [1,2-a] imidazoles
Figure BDA00001794363300191
In airtight container, under 170 ℃ with diethylenetriamines (0.56mL, 5.2mmol) and guanidine hydrochloride (0.50g 5.2mmol) stirs 6 hours.Afterwards, make fused mass be cooled to environmental temperature.Obtain white solid. 1H?NMR(400MHz,D 2O)δ3.33(m,4H),3.52(m,2H),3.62(m,2H)。
Instance 10. uses guanidine hydrochloride to synthesize 1,2,3,5,6,7-six hydrogen imidazos [1,2-a] pyrimidine
In airtight container, under 170 ℃ with N-(2-amino-ethyl)-1, the 3-propane diamine (0.65mL, 5.2mmol) and guanidine hydrochloride (0.50g 5.2mmol) stirs 6 hours.Afterwards, make fused mass be cooled to environmental temperature.Obtain white solid. 1H?NMR(400MHz,D 2O)δ1.80(p,2H,J=6Hz),3.12(t,4H,J=5.9Hz),3.37(m,2H),3.47(m,2H)。
Instance 11. uses guanidine hydrochloride Synthetic 2,3,4,6,7,8,9,10-octahydro pyrimido [1,2-a] [1,3] diazepine
Figure BDA00001794363300201
In airtight container, under 170 ℃ with spermidine (0.82mL, 5.2mmol) and guanidine hydrochloride (0.50g 5.2mmol) stirs 6 hours.Afterwards, make fused mass be cooled to environmental temperature. 1H?NMR(400MHz,D 2O)δ1.47(m,2H),1.57(m,2H),1.75(p,2H,J=5.7Hz),2.97(t,2H,J=5.5Hz),3.03(t,2H,J=5.8Hz),3.23(m,4H)。
Equivalent
The all material of being quoted in the application's case includes, but is not limited to patent and patent application case, regardless of the form of these documents and similar material, all incites somebody to action the mode of quoting in full clearly and is incorporated herein.At one or more document of incorporating into and similar material, include, but is not limited to define term, term usage, said technology etc., under or the situation of conflicting different, be as the criterion with the application's case with the application's case.
The chapter title that this paper uses is only started from organizational goal and should not be construed as and limits said subject matter by any way.
Though with reference to specific illustrative embodiment particular display and description the present invention, should be understood that under the situation that does not break away from the spirit and scope of the present invention, can make various changes to form of the present invention and details.Therefore, plan to advocate all embodiment in scope of the present invention and spirit and its equivalent.Unless otherwise mentioned, otherwise claims of the present invention and specification should not be regarded as the said sequence limit that receives key element.

Claims (69)

1. methods that prepare many ring guanidine compounds, it comprises the step that triamine compound is contacted with the reagent that is selected from by the following group that forms: guanidine, non-annularity guanidine compound, cyanamide, cyanogen group with imine moiety, melamine and melamine derivative.
2. method according to claim 1, many rings guanidine compound of its Chinese style V are to contact with the non-annularity guanidine compound of formula I through the triamine compound that makes formula IV to prepare:
Figure FDA00001794363200011
Wherein:
R aBe to be selected from the group that forms by following: hydrogen, optional through substituted aliphatic group, optional through substituted assorted aliphatic group, optional through substituted aryl and optional through substituted heteroaryl;
R cBe optional existence the, wherein R cWhen occurring, be independently selected from the group that forms by following: halogen, optional through substituted aliphatic group, optional through substituted assorted aliphatic group, optional through substituted aryl and optional, wherein two or more R through substituted heteroaryl at every turn cGroup can be randomly forms one or more and optionally contains 1 to 3 and be selected from the heteroatomic optional through replacing ring of oxygen, nitrogen or sulphur together with getting involved atom;
N is the integer of 1 to 4 (comprising 1 and 4);
M is the integer of 1 to 4 (comprising 1 and 4); And
R bWhen occurring, be independently selected from the group that forms by following: hydrogen, optional through substituted C at every turn 1-20Aliphatic group, optional through substituted aryl and nitrile.
3. method according to claim 2, wherein R bIt when occurring hydrogen or alkyl at every turn.
4. method according to claim 2, the non-annularity guanidine compound of wherein said formula I is a guanidine.
5. method according to claim 2, the non-annularity guanidine compound of wherein said formula I is the tetraalkyl guanidine.
6. method according to claim 2, the non-annularity guanidine compound of wherein said formula I is a TMG.
7. method according to claim 2, the non-annularity guanidine compound of wherein said formula I is salt or adduct form.
8. method according to claim 2, the non-annularity guanidine compound of wherein said formula I is carbonate form.
9. method according to claim 2, the non-annularity guanidine compound of wherein said formula I is a guanidine carbonate.
10. method according to claim 2, the non-annularity guanidine compound of wherein said formula I is a guanidine sulfate.
11. method according to claim 2, the non-annularity guanidine compound of wherein said formula I is a guanidine acetate.
12. method according to claim 2, the non-annularity guanidine compound of wherein said formula I is a guanidine nitrate.
13. method according to claim 2, the non-annularity guanidine compound of wherein said formula I is the p-methyl benzenesulfonic acid guanidine.
14. method according to claim 2, the non-annularity guanidine compound of wherein said formula I is a guanidine hydrochloride.
15. method according to claim 2, the non-annularity guanidine compound of wherein said formula I is a phosphoguanidine.
16. method according to claim 2, wherein R bIt when at least once occurring nitrile.
17. method according to claim 2, wherein R bBe nitrile when at least once occurring and all be independently selected from hydrogen or alkyl at all when other time occurs.
18. method according to claim 2, the non-annularity guanidine compound of wherein said formula I has formula Ia:
Figure FDA00001794363200021
19. method according to claim 2, the non-annularity guanidine compound of wherein said formula I is dicyandiamide.
20. method according to claim 1, many rings guanidine compound of its Chinese style V are to contact with the cyanogen group with imine moiety of formula II through the triamine compound that makes formula IV to prepare:
Figure FDA00001794363200031
Wherein:
R aBe to be selected from the group that forms by following: hydrogen, optional through substituted aliphatic group, optional through substituted assorted aliphatic group, optional through substituted aryl and optional through substituted heteroaryl;
R cBe optional existence the, wherein R cWhen occurring, be independently selected from the group that forms by following: halogen, optional through substituted aliphatic group, optional through substituted assorted aliphatic group, optional through substituted aryl and optional, wherein two or more R through substituted heteroaryl at every turn cGroup can be randomly forms one or more and optionally contains 1 to 3 and be selected from the heteroatomic optional through replacing ring of oxygen, nitrogen or sulphur together with getting involved atom;
N is the integer of 1 to 4 (comprising 1 and 4);
M is the integer of 1 to 4 (comprising 1 and 4); And
R bWhen occurring, be independently selected from the group that forms by following: hydrogen, optional through substituted C at every turn 1-20Aliphatic group and optional through substituted aryl.
21. method according to claim 20, the cyanogen group with imine moiety of wherein said formula II is a cyanamide.
22. method according to claim 20, wherein R bIt when occurring hydrogen or alkyl at every turn.
23. method according to claim 1, many rings guanidine compound of its Chinese style V are melamine or the melamine derivatives of triamine compound and formula III through making formula IV to be contacted and prepares:
Figure FDA00001794363200032
Wherein:
R aBe to be selected from the group that forms by following: hydrogen, optional through substituted aliphatic group, optional through substituted assorted aliphatic group, optional through substituted aryl and optional through substituted heteroaryl;
R cBe optional existence the, wherein R cWhen occurring, be independently selected from the group that forms by following: halogen, optional through substituted aliphatic group, optional through substituted assorted aliphatic group, optional through substituted aryl and optional, wherein two or more R through substituted heteroaryl at every turn cGroup can be randomly forms one or more and optionally contains 1 to 3 and be selected from the heteroatomic optional through replacing ring of oxygen, nitrogen or sulphur together with getting involved atom;
N is the integer of 1 to 4 (comprising 1 and 4);
M is the integer of 1 to 4 (comprising 1 and 4); And
R xAnd R yWhen occurring, be independently selected from the group that forms by following: hydrogen, optional through substituted C at every turn 1-20Aliphatic group and optional through substituted aryl.
24. method according to claim 23, wherein R xAnd R yWhen occurring, be hydrogen or alkyl independently at every turn.
25. method according to claim 23, many rings guanidine compound of wherein said formula V are to contact with melamine through the triamine compound that makes formula IV to prepare.
26. according to the described method of arbitrary claim in the claim 2,20 or 23, the triamine compound of wherein said formula IV has formula IVa:
Figure FDA00001794363200041
27. method according to claim 1, wherein said triamine compound are optional through substituted two (aminopropyl) amine.
28. method according to claim 1, wherein said triamine compound are optional through substituted two (amino-ethyl) amine.
29. method according to claim 1, wherein said triamine compound are optional through substituted 2, two (amino methyl) piperidines of 6-.
30. method according to claim 1, wherein said triamine compound are optional through substituted 2, two (amino-ethyl) piperidines of 6-.
31. method according to claim 1, wherein said triamine compound are optional through substituted 2, two (amino methyl) pyrrolidines of 5-.
32. method according to claim 1, wherein said triamine compound are optional through substituted 2, two (amino-ethyl) pyrrolidines of 5-.
33. method according to claim 1, wherein said triamine compound are optional through substituted N-(2-amino-ethyl)-1,3-propane diamine.
34. method according to claim 1, wherein said triamine compound are optional through substituted N-(2-amino-ethyl)-1,4-butanediamine.
35. method according to claim 1, wherein said triamine compound are optional through substituted N-(2-aminopropyl)-1,4-butanediamine.
36. according to the described method of arbitrary claim in the claim 2,20 or 23, wherein said triamine compound is to be selected from the group that is made up of following:
Figure FDA00001794363200051
37. according to the described method of arbitrary claim in the claim 2,20 or 23, wherein said triamine compound has following structure:
Figure FDA00001794363200062
38. according to the described method of arbitrary claim in the claim 2,20 or 23, wherein said triamine compound has following structure:
39. according to the described method of arbitrary claim in the claim 2,20 or 23, wherein said triamine compound has following structure:
Figure FDA00001794363200064
40. method according to claim 1, wherein said triamine compound contacts in the presence of solvent with said reagent.
41. method according to claim 1, wherein said triamine compound contacts under the situation that does not have solvent with said reagent.
42. method according to claim 1, it comprises the step of the mixture of said triamine compound of heating and said reagent in addition.
43., wherein said mixture is heated to the temperature between about 50 ℃ and about 250 ℃ according to the described method of claim 42.
44., wherein said mixture is heated to the temperature between about 80 ℃ and about 200 ℃ according to the described method of claim 42.
45., wherein said mixture is heated to the temperature between about 100 ℃ and about 180 ℃ according to the described method of claim 42.
46., wherein said mixture is heated to the temperature between about 140 ℃ and about 160 ℃ according to the described method of claim 42.
47. method according to claim 1, wherein said triamine compound contacts in the presence of promoter with said reagent.
48. according to the described method of claim 47, wherein said promoter is acid.
49. according to the described method of claim 48, wherein said acid is to be selected from the group that is made up of inorganic acid and sulfonic acid.
50. according to the described method of claim 49, wherein said promoter is sulfonic acid.
51. according to the described method of claim 48, wherein said acid is phosphoric acid.
52. according to the described method of claim 48, wherein said acid is sulfuric acid.
53. according to the described method of claim 50, wherein said sulfonic acid is to be selected from the group that is made up of following: Loprazolam, ethane sulfonic acid, p-methyl benzenesulfonic acid and TFMS.
54. according to the described method of claim 48, it comprises the step of handling the crude product that is produced by said reagent and the reaction of said triamine compound with highly basic in addition.
55. according to the described method of claim 54, wherein said highly basic is metal alkoxide.
56. according to the described method of claim 48, the mol ratio of wherein sour promoter and reagent is that about 2:1 is to about 2:2.
57. according to the described method of claim 48, the mol ratio of wherein sour promoter and reagent is about 1:1.
58. method according to claim 1, wherein the mol ratio of triamine compound and reagent is that about 2:1 is to about 2:2.
59. according to the described method of claim 58, wherein the mol ratio of triamine compound and reagent is about 1:1.
60. one kind is synthetic 1,5, the method for 7-three azabicyclos [5.5.0] last of the ten Heavenly stems-5-alkene (TBD), and it comprises the step that guanidine carbonate and pair (3-aminopropyl) amine are contacted in the presence of sulfonic acid.
61. according to the described method of claim 60, wherein said contact procedure comprises the pure reaction-ure mixture of heating.
62., wherein said mixture is heated to the temperature between about 80 ℃ and about 180 ℃ according to the described method of claim 61.
63. according to the described method of claim 60, wherein the mol ratio between guanidine carbonate, two (3-aminopropyl) amine and the said sulfonic acid is about 1:1:1.
64. according to the described method of claim 60, wherein said sulfonic acid comprises Loprazolam.
65. a synthetic l, 5, the method for 7-three azabicyclos [5.5.0] last of the ten Heavenly stems-5-alkene (TBD), it comprises the step that TMG and two (3-aminopropyl) amine are contacted in the presence of sulfonic acid.
66. according to the described method of claim 65, wherein said contact procedure comprises the pure reaction-ure mixture of heating.
67., wherein said mixture is heated to the temperature between about 80 ℃ and about 180 ℃ according to the described method of claim 66.
68. according to the described method of claim 65, wherein the mol ratio between guanidine carbonate, two (3-aminopropyl) amine and the said sulfonic acid is about 1:1:1.
69. according to the described method of claim 65, wherein said sulfonic acid comprises Loprazolam.
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